Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Bob T. Li

Research Funding: Roche/Genentech (Inst), AstraZeneca (Inst), Daiichi Sankyo (Inst), Hengrui Therapeutics (Inst), Amgen (Inst), Lilly (Inst), MORE Health (Inst), Bolt Biotherapeutics (Inst), Ambrx (Inst)

Patents, Royalties, Other Intellectual Property: US62/514,661 (Inst), US62/685,057 (Inst), Karger Publishers—Book royalty, Shanghai Jiao Tong University Press—Book royalty

Travel, Accommodations, Expenses: MORE Health, Jiangsu Hengrui Medicine

Uncompensated Relationships: Amgen, AstraZeneca, Genentech, Lilly, Boehringer Ingelheim, Daiichi Sankyo

No other potential conflicts of interest were reported.

Figures

FIG 1.

Long-term benefit and outcomes with sotorasib treatment. Kaplan-Meier plot of (A) PFS and (B) OS (median OS follow-up of 24.9 months [range, 0.7-35.9 months]) by central review, and (C) swimmer plot for phase I and phase II responders by central review (one patient with an ongoing response ended treatment because of patient request). BOR, best objective response; CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response.

FIG 2.

Association of long-term benefit and early progression with PD-L1 expression and genomic alterations: (A) PD-L1 tumor proportion score, (B) selected genomic alterations, (C) STK11 and KEAP1 mutations, and (D) Mutant versus wild-type STK11. CR, complete response; IHC, immunohistochemistry; PFS, progression-free survival; PR, partial response.